研究者詳細 - 曽我　朋義

論文 - 曽我　朋義

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Adenosine leakage from perforin-burst extracellular vesicles inhibits perforin secretion by cytotoxic T-lymphocytes

Tadokoro, H., Hirayama, A., Kudo, R., Hasebe, M., Yoshioka, Y., Matsuzaki, J., Yamamoto, Y., Sugimoto, M., Soga, T., Ochiya, T.

PLoS One 15 （ 4 ） e0231430 2020年04月

研究論文（学術雑誌）, 共著, 査読有り

Extracellular vesicles (EVs) in the tumor microenvironment facilitate intercellular communication. Cancer cell-derived EVs act as an immunosuppressor by transporting cargos and presenting transmembrane proteins. By contrast, CD8+ cytotoxic T-lymphocytes (CTLs) exert anti-cancer cytotoxicity via the pore-forming protein perforin. Here, we hypothesize that although EVs are destroyed by perforin, cancer cell-derived EVs might possess mechanisms that enable them to avoid this destruction. We used a breast cancer cell line, MDA-MB-231-luc-D3H2LN (D3H2LN), to generate EVs. Destruction of the EVs by perforin was demonstrated visually using atomic force microscopy. To investigate immunosuppressive metabolites within cancer cell-derived EVs, we performed metabolomic profiling of EVs from D3H2LN cells cultured for 48 h with or without IFN-γ, which induces metabolic changes in the cells. We found that both types of EV from IFN-γ treated D3H2LN cells and non-treated D3H2LN cells contained adenosine, which has immunosuppressive effects. When we exposed cancer cell-derived EVs to CTLs, perforin secretion by CTLs fell significantly. In addition, the decreases in perforin secretion were ameliorated by treatment with adenosine deaminase, which degrades extracellular adenosine. Taken together, these results suggest that after perforin secreted by CTLs disrupts the membrane of EVs, adenosine released from the EVs acts as an immunosuppressive metabolite by binding to the adenosine receptor on the CTL membrane. This mechanism provides a novel survival strategy using cancer cell-derived EVs.

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Sensory properties and metabolomic profiles of dry-cured ham during the ripening process

Sugimoto M., Sugawara T., Obiya S., Enomoto A., Kaneko M., Ota S., Soga T., Tomita M.

Food Res Int. 129 108850 2020年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09639969

Dry-cured ham with a long ripening period is a valuable product worldwide. Ripening time is a key determinant of the endogenous metabolites that characterize the flavor and taste of ham products. While various studies have analyzed the relationship between ripening duration and sensory characteristics, no studies have evaluated ham products produced in Japan. Here, we conducted time-course metabolomic profiling, taste sensor-based analyses, and sensory evaluations by non-trained consumers during ripening. Capillary electrophoresis-mass spectrometry was used to quantify non-volatile metabolites, such as amino acids, organic acids, and nucleotides. In an analysis of eight time-points during 680 days of ripening, the highest score for the after-taste of umami was observed on day 540, despite subtle changes in the scores for other properties. The concentrations of aspartic acid and glutamic acid relative to those of total amino acids were the highest at this point. This approach can contribute to the understanding of the relationship between the metabolite profile and ripening duration.

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Dynamic 13C Flux Analysis Captures the Reorganization of Adipocyte Glucose Metabolism in Response to Insulin

Quek, L.E., Krycer, J.R., Ohno, S., Yugi, K., Fazakerley, D.J., Scalzo, R., Elkington, S.D., Dai, Z., Hirayama, A., Ikeda, S., Shoji, F., Suzuki, K., Locasale, J.W., Soga, T., James, D.E., Kuroda, S.

iScience 23 （ 2 ） 100855 2020年02月

研究論文（学術雑誌）, 共著, 査読有り

Cellular metabolism is dynamic, but quantifying non-steady metabolic fluxes by stable isotope tracers presents unique computational challenges. Here, we developed an efficient 13C-tracer dynamic metabolic flux analysis (13C-DMFA) framework for modeling central carbon fluxes that vary over time. We used B-splines to generalize the flux parameterization system and to improve the stability of the optimization algorithm. As proof of concept, we investigated how 3T3-L1 cultured adipocytes acutely metabolize glucose in response to insulin. Insulin rapidly stimulates glucose uptake, but intracellular pathways responded with differing speeds and magnitudes. Fluxes in lower glycolysis increased faster than those in upper glycolysis. Glycolysis fluxes rose disproportionally larger and faster than the tricarboxylic acid cycle, with lactate a primary glucose end product. The uncovered array of flux dynamics suggests that glucose catabolism is additionally regulated beyond uptake to help shunt glucose into appropriate pathways. This work demonstrates the value of using dynamic intracellular fluxes to understand metabolic function and pathway regulation.

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A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity

Endoh, M., Baba, M., Endoh, T., Hirayama, A., Nakamura-Ishizu, A., Umemoto, T., Hashimoto, M., Nagashima, K., Soga, T., Lang, M., Schmidt, L.S., Linehan, W.M., Suda, T.

Cell Rep. 30 （ 6 ） 1823 - 1834 2020年02月

研究論文（学術雑誌）, 共著, 査読有り

The tumor suppressor folliculin (FLCN) suppresses nuclear translocation of TFE3, a master transcription factor for lysosomal biogenesis, via regulation of amino-acid-sensing Rag GTPases. However, the importance of this lysosomal regulation in mammalian physiology remains unclear. Following hematopoietic-lineage-specific Flcn deletion in mice, we found expansion of vacuolated phagocytes that accumulate glycogen in their cytoplasm, phenotypes reminiscent of lysosomal storage disorder (LSD). We report that TFE3 acts in a feedback loop to transcriptionally activate FLCN expression, and FLCN loss disrupts this loop, augmenting TFE3 activity. Tfe3 deletion in Flcn knockout mice reduces the number of phagocytes and ameliorates LSD-like phenotypes. We further reveal that TFE3 stimulates glycogenesis by promoting the expression of glycogenesis genes, including Gys1 and Gyg, upon loss of Flcn. Taken together, we propose that the FLCN-TFE3 feedback loop acts as a rheostat to control lysosome activity and prevents excessive glycogenesis and LSD-like phagocyte activation.

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The guanylate cyclase C agonist linaclotide ameliorates the gut-cardio-renal axis in an adenine-induced mouse model of chronic kidney disease

Nanto-Hara F., Kanemitsu Y., Fukuda S., Kikuchi K., Asaji K., Saigusa D., Iwasaki T., Ho H.J., Mishima E., Suzuki T., Suzuki C., Tsukimi T., Matsuhashi T., Oikawa Y., Akiyama Y., Kure S., Owada Y., Tomioka Y., Soga T., Ito S., Abe T.

Nephrol. Dial. Transplant. 35 （ 2 ） 250 - 264 2020年02月

研究論文（学術雑誌）, 共著, ISSN 09310509

Background: Cardiorenal syndrome is a major cause of mortality in patients with chronic kidney disease (CKD). However, the involvement of detrimental humoral mediators in the pathogenesis of cardiorenal syndrome is still controversial. Trimethylamine-N-oxide (TMAO), a hepatic metabolic product of trimethylamine generated from dietary phosphatidylcholine or carnitine derived by the gut microbiota, has been linked directly with progression of cardiovascular disease and renal dysfunction. Thus, targeting TMAO may be a novel strategy for the prevention of cardiovascular disease and chronic kidney disease.
Methods: Linaclotide, a guanylate cyclase C agonist, was administered to adenine-induced renal failure (RF) mice and changes in renal function and levels of gut-derived uremic toxins, as well as the gut microbiota community, were analyzed using metabolomic and metagenomic methods to reveal its cardiorenal effect.
Results: Linaclotide decreased the plasma levels of TMAO at a clinically used low dose of 10 μg/kg in the adenine-induced RF mouse model. At a high concentration of 100 μg/kg, linaclotide clearly improved renal function and reduced the levels of various uremic toxins. A reduction in TMAO levels following linaclotide treatment was also observed in a choline-fed pro-atherosclerotic model. Linaclotide ameliorated renal inflammation and fibrosis and cardiac fibrosis, as well as decreased the expression of collagen I, transforming growth factor-β, galectin-3 (Gal-3) and ST2 genes. Plasma levels of Gal-3 and ST2 were also reduced. Because exposure of cardiomyocytes to TMAO increased fibronectin expression, these data suggest that linaclotide reduced the levels of TMAO and various uremic toxins and may result in not only renal, but also cardiac, fibrosis. F4/80-positive macrophages were abundant in small intestinal crypts in RF mice, and this increased expression was decreased by linaclotide. Reduced colonic claudin-1 levels were also restored by linaclotide, suggesting that linaclotide ameliorated the 'leaky gut' in RF mice. Metagenomic analysis revealed that the microbial order Clostridiales could be responsible for the change in TMAO levels.
Conclusion: Linaclotide reduced TMAO and uremic toxin levels and could be a powerful tool for the prevention and control of the cardiorenal syndrome by modification of the gut-cardio-renal axis.

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Lactate production is a prioritized feature of adipocyte metabolism

Krycer, J.R., Quek, L.E., Francis, D.J., Fazakerley, S.D., Elkington, S., Diaz-Vegas, A., Cooke, K.C., Weiss, F.C., Duan, X., Kurdyukov, S., Zhou, P.X., Tambar, U.,K. Hirayama, A., Ikeda, S., Kamei, Y., Soga, T., Cooney, G.J., James, D.E.

J Biol Chem. 295 （ 1 ） 83 - 98 2020年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00219258

Adipose tissue is essential for whole-body glucose homeostasis, with a primary role in lipid storage. It has been previously observed that lactate production is also an important metabolic feature of adipocytes, but its relationship to adipose and whole-body glucose disposal remains unclear. Therefore, using a combination of metabolic labeling techniques, here we closely examined lactate production of cultured and primary mammalian adipocytes. Insulin treatment increased glucose uptake and conversion to lactate, with the latter responding more to insulin than did other metabolic fates of glucose. However, lactate production did not just serve as a mechanism to dispose of excess glucose, because we also observed that lactate production in adipocytes did not solely depend on glucose availability and even occurred independently of glucose metabolism. This suggests that lactate production is prioritized in adipocytes. Furthermore, knocking down lactate dehydrogenase specifically in the fat body of Drosophila flies lowered circulating lactate and improved whole-body glucose disposal. These results emphasize that lactate production is an additional metabolic role of adipose tissue beyond lipid storage and release.

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Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression

McCarthy, MT., Lin, D., Soga, T., Adam, J., O'Callaghan, CA.

Eur. J. Immunol. 50 （ 1 ） 130 - 137 2020年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00142980

Inosine pranobex (IP) is a synthetic immunomodulating compound, indicated for use in the treatment of human papillomavirus-associated warts and subacute sclerosing panencephalitis. Previous studies demonstrate that the immunomodulatory activity of IP is characterized by enhanced lymphocyte proliferation, cytokine production, and NK cell cytotoxicity. The activation of NKG2D signaling on NK cells, CD8+ T cells, and γδ T cells also produces these outcomes. We hypothesized that IP alters cellular immunity through the induction of NKG2D ligand expression on target cells, thereby enhancing immune cell activation through the NKG2D receptor. We tested this hypothesis and show that exposure of target cells to IP leads to increased expression of multiple NKG2D ligands. Using both targeted metabolic interventions and unbiased metabolomic studies, we found that IP causes an increase in intracellular concentration of purine nucleotides and tricarboxylic acid (TCA) cycle intermediates and NKG2D ligand induction. The degree of NKG2D ligand induction was functionally significant, leading to increased NKG2D-dependent target cell immunogenicity. These findings demonstrate that the immunomodulatory properties of IP are due to metabolic activation with NKG2D ligand induction.

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Characterization of cancer omics and drug perturbations in panels of lung cancer cells

Suzuki, A., Onodera, K., Matsui, K., Seki, M., Esumi, H., Soga, T., Sugano, S., Kohno, T., Suzuki, Y., Tsuchihara, K.

Sci Rep 9 （ 1 ） 19529 2019年12月

研究論文（学術雑誌）, 共著, 査読有り

To better understand the disruptions of transcriptional regulations and gene expression in lung cancers, we constructed a multi-omics catalogue of the responses of lung cancer cells to a series of chemical compounds. We generated and analyzed 3,240 RNA-seq and 3,393 ATAC-seq libraries obtained from 23 cell lines treated with 95 well-annotated compounds. To demonstrate the power of the created multi-omics resource, we attempted to identify drugs that could induce the designated changes alone or in combination. The basal multi-omics information was first integrated into co-expression modules. Among these modules, we identified a stress response module that may be a promising drug intervention target, as new combinations of compounds that could be used to regulate this module and the consequent phenotypic appearance of cancer cells have been identified. We believe that the multi-omics profiles generated in this study and the strategy used to stratify them will lead to more rational and efficient development of anticancer drugs.

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Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment

Annan, DA., Maishi, N., Soga T., Dawood, R. Li, C., Kikuchi, H., Hojo, T., Morimoto, M., Kitamura, T., Alam, MT., Minowa, K., Shinohara, N., Nam, JM., Hida, Y., Hida, K.

Cell Commun. Signal. 17 （ 1 ） 169 2019年12月

研究論文（学術雑誌）, 共著, 査読有り

Background: Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood.
Methodology: The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia.
Results: The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis.
Conclusion: These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy. Video Abstract.

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Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation

Fujiwara, H., Tateishi, K., Misumi, K., Hayashi, A., Igarashi, K, Kato, H., Nakatsuka, T., Suzuki, N., Yamamoto, K., Kudo, Y., Hayakawa, Y., Nakagawa, H., Tanaka, Y., Ijichi, H., Kogure, H, Nakai, Y, Isayama, H., Hasegawa, K., Fukayama, M., Soga, T., Koike, K..

Sci. Rep. 9 （ 1 ） 18859 2019年12月

研究論文（学術雑誌）, 共著, 査読有り

Metabolism is a critical regulator of cell fate determination. Recently, the significance of metabolic reprogramming in environmental adaptation during tumorigenesis has attracted much attention in cancer research. Recurrent mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes have been identified in several cancers, including intrahepatic cholangiocarcinoma (ICC). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which affects the activity of multiple α-KG-dependent dioxygenases including histone lysine demethylases. Although mutant IDH can be detected even in the early stages of neoplasia, how IDH mutations function as oncogenic drivers remains unclear. In this study, we aimed to address the biological effects of IDH1 mutation using intrahepatic biliary organoids (IBOs). We demonstrated that mutant IDH1 increased the formation of IBOs as well as accelerated glucose metabolism. Gene expression analysis and ChIP results revealed the upregulation of platelet isoform of phosphofructokinase-1 (PFKP), which is a rate-limiting glycolytic enzyme, through the alteration of histone modification. Knockdown of the Pfkp gene alleviated the mutant IDH1-induced increase in IBO formation. Notably, the high expression of PFKP was observed more frequently in patients with IDH-mutant ICC compared to in those with wild-type IDH (p < 0.01, 80.9% vs. 42.5%, respectively). Furthermore, IBOs expressing mutant IDH1 survived the suppression of ATP production caused by growth factor depletion and matrix detachment by retaining high ATP levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Our findings provide a systematic understanding as to how mutant IDH induces tumorigenic preconditioning by metabolic rewiring in intrahepatic cholangiocytes.

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Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection

Osada-Oka, M., Goda, N., Saiga, H., Yamamoto, M., Takeda, K., Ozeki, Y., Yamagchi, T., Soga, T., Tateishi, Y., Miura, K., Okuzaki, D., Kobayashi, K., *Matsumoto, S.

Int. Immunol. 31 （ 12 ） 781 - 793 2019年11月

研究論文（学術雑誌）, 共著, 査読有り

Macrophages are major components of tuberculosis (TB) granulomas and are responsible for host defenses against the intracellular pathogen, Mycobacterium tuberculosis. We herein showed the strong expression of hypoxia-inducible factor-1α (HIF-1α) in TB granulomas and more rapid death of HIF-1α-conditional knockout mice than wild-type (WT) mice after M. tuberculosis infection. Although interferon-γ (IFN-γ) is a critical host-protective cytokine against intracellular pathogens, HIF-1-deficient macrophages permitted M. tuberculosis growth even after activation with IFN-γ. These results prompted us to investigate the role of HIF-1α in host defenses against infection. We found that the expression of lactate dehydrogenase-A (LDH-A) was controlled by HIF-1α in M. tuberculosis-infected macrophages IFN-γ independently. LDH-A is an enzyme that converts pyruvate to lactate and we found that the intracellular level of pyruvate in HIF-1α-deficient bone marrow-derived macrophages (BMDMs) was significantly higher than in WT BMDMs. Intracellular bacillus replication was enhanced by an increase in intracellular pyruvate concentrations, which were decreased by LDH-A. Mycobacteria in phagosomes took up exogenous pyruvate more efficiently than glucose, and used it as the feasible carbon source for intracellular growth. These results demonstrate that HIF-1α prevents the hijacking of pyruvate in macrophages, making it a fundamental host-protective mechanism against M. tuberculosis.

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A metabolic profile of routine needle biopsies identified tumor type specific metabolic signatures for breast cancer stratification: a pilot study

Harada-Shoji, N., Soga, T., Tada, H., Miyashita, M., Harada, M., Watanabe, G., Hamanaka, Y., Sato, A., Suzuki, T., Suzuki, A., Ishida, T.

Metabolomics 15 （ 11 ） 147 2019年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15733882

Introduction: Metabolomics has recently emerged as a tool for understanding comprehensive tumor-associated metabolic dysregulation. However, only limited application of this technology has been introduced into the clinical setting of breast cancer.
Objectives: The aim of this study was to determine the feasibility of metabolome analysis using routine CNB/VAB samples from breast cancer patients and to elucidate metabolic signatures using metabolic profiling.
Methods: After breast cancer screenings, 20 consecutive patients underwent CNB/VAB, and diagnosed with benign, DCIS and IDC by histology. Metabolome analysis was performed using CE-MS. Differential metabolites were then analyzed and evaluated with MetaboAnalyst 4.0.
Results: We measured 116-targeted metabolites involved in energy metabolism. Principal component analysis and unsupervised hierarchical analysis revealed a distinct metabolic signature unique to namely "pure" IDC samples, whereas that of DCIS was similar to benign samples. Pathway analysis unveiled the most affected pathways of the "pure" IDC metabotype, including "pyrimidine," "alanine, aspartate, and glutamate" and "arginine and proline" pathways.
Conclusions: Our proof-of-concept study demonstrated that CE-MS-based CNB/VAB metabolome analysis is feasible for implementation in routine clinical settings. The most affected pathways in this study may contribute to improved breast cancer stratification and precision medicine.

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MITF controls the TCA cycle to modulate the melanoma hypoxia response

Louphrasitthiphol P., Ledaki I., Chauhan J., Falletta P., Siddaway R., Buffa FM., Mole DR., Soga T., Goding CR.

Pigment. Cell Melanoma. Res. 32 （ 6 ） 792 - 808 2019年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 17551471

In response to the dynamic intra-tumor microenvironment, melanoma cells adopt distinct phenotypic states associated with differential expression of the microphthalmia-associated transcription factor (MITF). The response to hypoxia is driven by hypoxia-inducible transcription factors (HIFs) that reprogram metabolism and promote angiogenesis. HIF1α indirectly represses MITF that can activate HIF1α expression. Although HIF and MITF share a highly related DNA-binding specificity, it is unclear whether they co-regulate subset of target genes. Moreover, the genomewide impact of hypoxia on melanoma and whether melanoma cell lines representing different phenotypic states exhibit distinct hypoxic responses is unknown. Here we show that three different melanoma cell lines exhibit widely different hypoxia responses with only a core 23 genes regulated in common after 12 hr in hypoxia. Surprisingly, under hypoxia MITF is transiently up-regulated by HIF1α and co-regulates a subset of HIF targets including VEGFA. Significantly, we also show that MITF represses itself and also regulates SDHB to control the TCA cycle and suppress pseudo-hypoxia. Our results reveal a previously unsuspected role for MITF in metabolism and the network of factors underpinning the hypoxic response in melanoma.

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Association between dyslipidemia and plasma levels of branched-chain amino acids in the Japanese population without diabetes mellitus

Fukushima, K., Harada, S., Takeuchi, A., Kurihara, A., Iida, M., Fukai, K., Kuwabara, K., Kato, S., Matsumoto, M., Hirata, A., Akiyama, M., Tomita, M., Hirayama, A., Sato, A., Suzuki, C., Sugimoto, M., Soga, T., Sugiyama, D., Takebayashi, T.

J. Clini. Lipidol 13 （ 6 ） 932 - 939 2019年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 19332874

Background: Branched-chain amino acids (BCAAs) play a key role in energy homeostasis.
Objective: We aimed to investigate the association between plasma BCAA levels and dyslipidemia in the Japanese population without diabetes mellitus.
Methods: This cross-sectional study included 4952 participants without diabetes mellitus, enrolled in the Tsuruoka Metabolomic Cohort Study. Plasma BCAA levels were measured by capillary electrophoresis-mass spectrometry. Correlations between lipid and BCAA profiles were evaluated by sex-stratified multiple linear regression analyses, after adjusting for confounders. Logistic regression was used to identify associations between BCAAs and metabolic dyslipidemia (MD) defined as triglyceride levels ≥150 mg/dL, high-density lipoprotein cholesterol levels ≤40 mg/dL for men and ≤50 mg/dL for women, or low-density lipoprotein cholesterol (LDL-C) levels ≥140 mg/dL.
Results: In both sexes, the levels of individual BCAAs and the total BCAA levels correlated positively with triglyceride levels and negatively with high-density lipoprotein cholesterol levels. Valine, leucine, and total BCAA levels were weakly and positively correlated with LDL-C levels. Increased BCAA levels showed positive associations with MD. However, associations between BCAAs and elevated LDL-C levels were unclear. Furthermore, the associations between BCAA levels and MD regardless of fasting blood sugar (FBS) levels (high or low). Although valine, leucine, and total BCAA levels were weakly associated with elevated LDL-C levels in the high-FBS group, no such association was observed in the low-FBS group.
Conclusions: BCAAs might be associated with MD independently of the FBS level and might play an important role in lipid metabolism and dyslipidemia.

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Metabolome Analysis Reveals Dermal Histamine Accumulation in Murine Dermatitis Provoked by Genetic Deletion of P-Glycoprotein and Breast Cancer Resistance Protein

Hashimoto N., Nakamichi N., Nanmo H., Kimura K.i., Masuo Y., Sakai Y., Schinkel A.H., Sato S., Soga T., Kato Y.

Pharm. Res. 36 （ 11 ） 158 2019年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 07248741

Purpose: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are xenobiotic transporters which pump out variety types of compounds, but information on their interaction with endogenous substrates in the skin is limited. The purpose of the present study was to clarify possible association of these transporters in dermal accumulation of inflammatory mediators. Methods: Dermatitis model was constructed by repeated topical application of oxazolone in wild-type, and P-gp and BCRP gene triple knockout (Mdr1a/1b/Bcrp−/−) mice to observe difference in phenotype. Target metabolome analysis of 583 metabolites was performed using skin and plasma. Results: Dermatitis and scratching behavior in dermatitis model of Mdr1a/1b/Bcrp−/− mice were more severe than wild-type mice, suggesting protective roles of these transporters. This hypothesis was supported by the metabolome analysis which revealed that concentration of histamine and other dermatitis-associated metabolites like urate and serotonin in the dermatitis skin, but not normal skin, of Mdr1a/1b/Bcrp−/− mice was higher than that of wild-type mice. Gene expression of P-gp and BCRP was reduced in oxazolone-treated skin and the skin of patients with atopic dermatitis or psoriasis. Conclusions: These results suggest possible association of these efflux transporters with dermal inflammatory mediators, and such association could be observed in the dermatitis skin.

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Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma

Nakagawa M., Nakatani F., Matsunaga H., Seki T., Endo M., Ogawara Y., Machida Y., Katsumoto T., Yamagata K., Hattori A., Fujita S., Aikawa Y., Ishikawa T., Soga T., Kawai A., Chuman H., Yokoyama N., Fukushima S., Yahiro K., Kimura A., Shimada E., Hirose T., Fujiwara T., Setsu N., Matsumoto Y., Iwamoto Y., Nakashima Y., Kitabayashi I.

Oncogene 38 （ 42 ） 6835 - 6849 2019年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09509232

Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in ~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.

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Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2

Osawa T., Shimamura T., Saito K., Hasegawa Y., Ishii N., Nishida M., Ando R., Kondo A., Anwar M., Tsuchida R., Hino S., Sakamoto A., Igarashi K., Saitoh K., Kato K., Endo K., Yamano S., Kanki Y., Matsumura Y., Minami T., Tanaka T., Anai M., Wada Y., Wanibuchi H., Hayashi M., Hamada A., Yoshida M., Yachida S., Nakao M., Sakai J., Aburatani H., Shibuya M., Hanada K., Miyano S., Soga T., Kodama T.

Cell Rep. 29 （ 1 ） 89 - 103.e7 2019年10月

研究論文（学術雑誌）, 共著, 査読有り

Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.

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Fructose Increases the Activity of Sodium Hydrogen Exchanger in Renal Proximal Tubules that is Dependent on Ketohexokinase

Hayasaki, T., Ishimoto, T., Doke, T., Hirayama, A., Soga, T., Furuhashi, K., Kato, N., Kosugi, T., Tsuboi, N., Lanaspa, MA., Johnson, RJ., Maruyama, S., Kadomatsu, K.

J. Nutr. Biochem. 71 （ - ） 54 - 62 2019年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09552863

High fructose intake has been known to induce metabolic syndrome in laboratory animals and humans. Although fructose intake enhances sodium reabsorption and elevates blood pressure, role of fructose metabolism in this process has not been studied. Here we show that by ketohexokinase - the primary enzyme of fructose - is involved in regulation of renal sodium reabsorption and blood pressure via activation of the sodium hydrogen exchanger in renal proximal tubular cells. First, wild-type and ketohexokinase knockout mice (Male, C57BL/6) were fed fructose water or tap water with or without a high salt diet. Only wild type mice fed the combination of fructose water and high salt diet displayed increased systolic blood pressure and decreased urinary sodium excretion. In contrast, ketohexokinase knockout mice were protected. Second, urinary sodium excretion after intraperitoneal saline administration was reduced with the decreased phosphorylation of sodium hydrogen exchanger 3 in fructose-fed WT; these changes were not observed in the ketohexokinase knockout mice, however. Third, knockdown of ketohexokinase attenuated fructose-mediated increases of NHE activity with decreased cAMP levels in porcine renal proximal tubular cells (LLC-PK1). In conclusion, fructose metabolism by ketohexokinase increases sodium hydrogen exchanger activity in renal proximal tubular cells via decreased intracellular cAMP level, resulting in increased renal sodium reabsorption and blood pressure in mice.
Keywords: Blood pressure; Fructose; Ketohexokinase; Kidney; NHE3; Sodium reabsorption.
Copyright © 2019 Elsevier Inc. All rights reserved.

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BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

Yoneshiro T., Wang, Q., Tajima K., Matsushita M., Maki H., Igarashi K., Dai Z., White PJ., McGarrah RW., Ilkayeva OR., Deleye Y., Oguri Y., Kuroda M., Ikeda K., Li H., Ueno A., Ohishi M., Ishikawa T., Kim K., Chen Y., Sponton CH., Pradhan RN., Majd H., Greiner VJ., Yoneshiro M., Brown Z., Chondronikola M., Takahashi H., Goto T., Kawada T., Sidossis L., Szoka FC., McManus MT., Saito M., Soga T., Kajimura S.

Nature 572 （ 7771 ） 614 - 619 2019年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00280836

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.

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Metabolomic profiling reveals salivary hypotaurine as a potential early detection marker for medication-related osteonecrosis of the jaw

Yatsuoka, W., Ueno, T., Miyano, K., Uezono, Y., Enomoto, A., Kaneko, M., Ota, S., Soga, T., Sugimoto, M., Ushijima, T.

PLoS ONE 14 （ 8 ） e0220712 2019年08月

研究論文（学術雑誌）, 共著, 査読有り

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse event of bone-modifying agents used to prevent bone complications in cancer patients with bone metastasis. Currently, early treatment is the only way to prevent further progression, as the pathogenesis of MRONJ has not yet been elucidated, and a standard treatment has not been established. The aim of this study was to identify a marker for early detection marker of MRONJ by exploring substances in saliva specific to MRONJ at an early stage. We collected salivary samples from 17 patients with MRONJ and conducted metabolomic analyses using capillary electrophoresis mass spectrometry for non-targeted analysis of hydrophilic metabolites. In the screening cohort, we compared the saliva of patients with stage ≥1 advanced MRONJ (n = 9) with that of controls without MRONJ before chemotherapy (n = 9). The top 5 most elevated salivary metabolites were histamine, 3-(4-hydroxyphenyl)propionate, malonate, carnosine, and hypotaurine. In the validation cohort, we analyzed additional patients with stage ≥1 advanced MRONJ (n = 8) and controls without MRONJ after chemotherapy (n = 9), confirming a significant 2.28-fold elevation in the salivary concentration of hypotaurine. These results revealed elevated salivary hypotaurine concentration as a potential marker for the early detection of MRONJ.

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